Preparation of homo- and heteroaryl-2-aniline ketones



United States Patent 3,428,644 PREPARATION OF HOMO- AND HETEROARYL-Z- ANILINE KETONES Paul Aeberli, Madison, and William J. Honlihan, Mountain Lakes, N.J., assignors to Sandoz Inc., Hanover, NJ. No Drawing. Filed June 28, 1965, Ser. No. 467,690 US. Cl. 260296 8 Claims Int. Cl. C07d 31/42, 27/20, 63/10 ABSTRACT OF THE DISCLOSURE Homoand heteroaryl-Z-aniline ketones (I) useful as intermediates for pharmaceuticals, are prepared by contacting a 3-homoor heteroaryloxindole with a base to form a salt which is then reacted'with oxygen to form I.

The present invention is directed to the preparation of intermediates for pharmaceuticals. The intermediates are compounds of the formula NHz (I) wherein R is either a chlorine atom (C1); a hydrogen atom (-H); hydroxyl (-OH); lower alkyl having no abranching, e.g. methyl, ethyl, propyl and butyl; lower .alkoxy having no a-branching, e.g. methoxy, ethoxy, propoxy and butoxy; or, together with R methylenedioxy (OCH O);

R is either a chlorine atom (---Cl); 2 hydrogen atom (H); hydroxyl (OH); lower alkyl having no abranching, e.g. methyl, ethyl, propyl and butyl; lower alkoxy having no oc-blanChiIlg, e.g. methoxy, ethoxy, propoxy and butoxy; or, taken together with R, methylenedioxy (OCH O);

R is either 2-furyl, S-furyl, Z-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, l-naphthyl, Z-naphthyl These intermediates are useful in the preparation of, e.g., benzodiazepines, such as 7-chloro-2-methylamino-5- pheny1-3H-l,4-benzodiazepine-4-oxide hydrochloride and benzodiazepine derivatives disclosed in Belgian Patent 615,194, which are known and of known pharmacological utility. They are useful, also, in preparing related compounds of the same general class and in investigating changes in pharmacological effects brought about by corresponding changes in structure.

It is an object of this invention to prepare compounds I from materials which are readily available or readily prepared from available compounds. It is a further object of this invention to prepare polysu-bstituted systems of Formula I. A still further object of this invention is to prepare compounds of Formula I wherein R is a phenyl group containing strongly electronegative substituents, e.g. NO SO R' and ---CF;,. These and other objectives .are satisfied by the process of this invention.

The instant process is represented by the following reaction scheme:

wherein each of R, R and R? has its above-ascribed meaning; and M is either a lithium ion (Lia sodium ion (Na' or a potassium ion (K' Compounds III are prepared from corresponding compounds H according to the procedures described in US. Patent 2,759,935. Compounds H are either known or are prepared by known procedures from available compounds.

Compound I is, prepared from the corresponding compound III in a solvent, e.g. dimethylformamide (DMF), dimethylacetamide (DMA) and a polar inert solvent, such as ethanol. The preferred temperature range is from 20 to C. Either air or oxygen (0 is employed as the oxygen source.

The following examples illustrate the invention, all temperatures being in degrees centigrade, parts and percentages being by weight unless otherwise specified, the relationship between parts by weight and parts by volume being the same as that between the kilogram and the liter.

Example l.2-aminobenzophenone Charge a flask (equipped with a stirrer, condenser, gas inlet and drying tube) with 2.5 parts (0.012 mole) of 3-phenyloxindole, 1.5 parts (0.03 mole) of sodium hydride (50% dispersion in mineral oil) and 125 parts by volume of absolute DMF. Stir the thus-obtained mixture at room temperature (20) while bubbling dry air below the surface of said mixture. Discontinue the gassing after 16 hours, and admix the thus-gassed material (a dark reddish brown mixture) with ice Water.

Filter the resultant semi-solid, wash same with water and then dissolve same in chloroform. Wash the chloroform extract with 2 N hydrochloric acid and saturated (aq) sodium chloride. Dry the thus-washed material over sodium sulfate and concentrate the resultant to obtain 1.4 parts of title compound, melting point (M.P.) 97 to 100.

Replacing the S-phenyloxindole with an equivalent of either 3-(2-furyl)oxindole, 3-(3-thienyl)oxindole, 3-(4- pyridyl)oxindole or 3-(1-naphthyl)oxindole results in the preparation, in similar manner, of the corresponding compound I.

Example 2.2-amino-S-chlorobenzophenone Charge a flask (equipped with a magnetic stirring bar, thermometer, drying tube and a gas inlet tube) with 2.5 parts (0.01 mole) of S-chloro-3-phenyloxindole, 0.5 part (0.012 mole) of sodium hydroxide and 125 parts by volume of absolute DMF. Stir the resulting mixture, heat same to 50 and pass a stream of dry air through the thus-heated mixture for 15 hours. Then pour the obtained reddish-brown mixture onto 300 parts by volume of ice water and adjust the pH to 2.0. Filter the thus-obtained solid, wash same with water and then dissolve same in chloroform. Wash the resulting chloroform solution with saturated (aq) sodium chloride. Dry the thus-washed solution over sodium sulfate, filter and concentrate in vacuo on a rotary evaporator. Distil the resultant residue under a high vacuum to obtain 1.5 parts of title compound, M.P. 88 to 90.

Replacing the S-c'hloro-3-phenyloxindole with an equivalent of either 3-(3-furyl)-5-hydroxyoxindole, 5,6-dimethyl-3-(2-thienyl)-oxindole, 6-methoxy-3-(2-pyridyl) oxindole, 5,6-methylenedioxy-3-(3-pyridyl)oxindole or 6- chloro-3-(2-naphthyl)oxindole results in the Preparation, in similar manner, of the corresponding compound 1.

Example 3.-methoxy-2-aminobenzophenone parts (0.006 mole) of 5-methoxy-3-phenyloxindole, 0.3 part (0.008 mole) of sodium hydroxide and 75 parts by volume of absolute DMF. Stir the resulting mixture, heat same to 50 and pass a stream of dry air through the thus-heated mixture for 15 hours. Then pour the obtained reddish-brown mixture onto 300 parts by volume of ice water and adjust the pH to 2.0. Filter the thus-obtained solid, wash same with water and then dissolve same in chloroform. Wash the resulting chloroform solution with saturated (aq) sodium chloride. Dry the thus-washed solution over sodium sulfate, filter and concentrate in vacuo on a rotary evaporator. Distil the resultant residue under a high vacuum to obtain 1.5 parts of title compound, M.P. 67 to 69.

Replacing the S-methoxy-3-phenyloxindole with an equivalent of either 5-ethyl-3-(2-chloro-4-ethyl)phenyloxindole, 6-ethyl-3-(3-fluoro-4-phenyl)phenyloxindole, 5- ethoxy-3 (2,4-dimethyl) -phenyloxindole, 6-ethoxy-3- (3 ,5 dimethoxy phenyloxindole, 6-hydroxy-3- (4-ethylsulfonyl- 2-nitro)phenyl0xindole, 3 (3-phenyl-5-trifluoromethyl) phenyl-S-propyloxindole, 6-methyl-3-(3,5-dimethylsulfonyl)phenyloxindole or 5-methyl-3-(4-ethoxy-2-phenylsulfonyl)phenyloxindole results in the preparation, in similar manner, of the corresponding compound I.

The invention and its advantages are readily apparent from the foregoing description. Various changes may be made in the starting materials and the process variables without departing from the spirit and the scope of the invention or sacrificing its material advantages. The embodiments hereinbefore set forth are merely illustrative.

What is claimed is:

1. A process for the preparation of a compound of the formula wherein each of R and R is, independently, a member selected from the group consisting of a hydrogen atom, hydroxy, a chlorine atom, lower alkyl having no tat-branching, and lower alkoxy having no tat-branching, and taken together, methylenedioxy; and

R is a member selected from the group consisting of fury], thienyl, pyridyl, 1- or 2-naphthyl and a function of the formula wherein each of R R, R and R is, independently,

a member selected from the group consisting of a hydrogen atom, a halogen atom having an atomic weight of from 19 to 36, lower alkyl having no a-branching, lower alkoxy having no a-branching, nitro, trifiuoromethyl, phenyl and --SO R'; with the proviso that a plurality of trifiuoromethyl, phenyl, nitro and SO R' groups are not bound to adjacent carbon atoms; not more than two of R R R and R being other than hydrogen; and

R is a member selected from the group consisting of lower alkyl having no a-branching and phenyl R, R and R are as defined above, and M is a member selected from the group consisting of a 4. A process according to claim 3 wherein each of R, R R R, R and R is a hydrogen atom.

5. A process according to claim 3 wherein each of R, R R R and R is a hydrogen atom and R is a chlorine atom.

6. A process according to claim 2 wherein each of R, R R R and R is a hydrogen atom and R is methoxy. 7. A process according to claim 1 wherein R is thienyl. 8. A process according to claim 1 wherein R is pyridyl.

References Cited UNITED STATES PATENTS 8/1956 Specter 260247.2 1/1967 Sternbach et a1 260591 HENRY R. JILES, Primary Examiner.

A. L. ROTMAN, Assistant Examiner.

US. Cl. X.R. 

